The method of delivering drugs by inhalation has been used for several years, and is the mainstay of the treatment of disorders which limit the respiratory flow, such as asthma and chronic bronchitis.
The advantages of inhalation over the systemic route include the fact that the drug is released directly at the site of action, thus preventing systemic side effects and resulting in a faster clinical response and a higher therapeutic index.
These advantages have also been used in the pulmonary administration of drugs designed to produce a systemic effect in the treatment of non-pulmonary disorders. Drugs administered by the inhalation route are dispensed in the form of powders by powder inhalers, as solutions or suspensions in fluorinated propellant by pressurized metered dose inhalers (MDI), or as aqueous solutions or suspensions by suitable ultrasound or compressed-air nebulisers. These drugs belong to different therapeutic classes: they are represented in particular by drugs designed for the treatment of respiratory diseases, such as antibiotics, corticosteroids, mucosecretolytics, anticholinergics and β2-adrenergic receptor agonists.
The aerosol therapy is mainly used to treat inflammatory disorders; in this field, a special place is held by corticosteroids such as beclomethasone dipropionate (BDP), mometasone furoate, flunisolide, budesonide, ciclesonide and fluticasone propionate. These drugs are generally administered in micronised form in suspension in an aqueous vehicle or in a propellant. The drug is inhaled in aerosol form, i.e. in the form of a dispersion of solid particles in a gaseous medium. The efficacy of this form of administration depends on the deposit of a sufficient amount of particles at the site of action.
If peripheral areas of the respiratory tree, such as the alveoli, are to be reached, as in the case of bronchopulmonary formulations, one of the most important parameters is the particle size, which must be lower than or equal to 5-6 micron. This size is quantified by measuring a characteristic sphere-equivalent diameter, known as the median aerodynamic diameter (MAD), which expresses the ability of particles to be transported in suspension in an airstream. Another parameter widely utilised is the mass median aerodynamic diameter (MMAD) which corresponds to the MAD of the 50 percent by weight of the particles.
Particles with a larger MAD are ineffective, because they are deposited in the oropharyngeal cavity, and are therefore unable to reach the terminal branches of the respiratory tree. They can also give rise to local side effects, or may be absorbed through the mucous membranes and give rise to systemic side effects.
Particles of suitable size for inhalation treatment are not generally obtainable by simple crystallisation from a solution. In order to obtain high crystallinity and adequate purity, and to minimise the residual solvent content, products for pharmaceutical use are crystallised slowly; however, particles with a non-uniform size which exceeds the upper limit specified above are normally produced under these conditions. On the other hand, in order to obtain a fine precipitate, the crystallisation process must be rapid but in this case it is very difficult to identify the relevant parameters such as solvent, concentration, temperature and time, so as to obtain a completely crystalline product and/or avoid the inclusion of impurities in the crystals. Products designed for inhalation therefore normally undergo a micronization treatment. This treatment is usually performed in a fluid energy mill constituted by a chamber with a circular or other geometrical shape (e.g. a flattened ring), with a lateral extension into which the active ingredient to be micronised is introduced. A fluid, generally air or nitrogen, is injected at high pressure through nozzles in the bottom of the unit. The solid material is introduced into the fluid stream, and as a result of the high turbulence created, develops friction and impact between particles and between the particles and the chamber walls, which leads to a reduction in their size. A centrifugal classifier (cyclone) is incorporated into the apparatus so that the particles are retained until they reach the desired degree of fineness. Solid materials, especially steroids, usually contain particles with sizes of up to 150 micron before being micronised. In order to obtain particles of suitable dimensions for pulmonary administration (5-6 micron), the parameters involved (fluid pressure, chamber temperature, time of solid material addition and micronization time) must be regulated on the basis of the characteristics of the active ingredient (initial size, and hardness of crystal). In general, the larger their size and the harder the crystal, the more time the particles must remain in the micronization chamber, and/or the higher the flow rate and pressure of the fluid used need to be. The micronization of steroids such as BDP is usually conducted at a pressure of between 10 and 12 bar, for approx. 30 minutes.
However, micronization techniques have some drawbacks, including the fact that the percentage of particles obtained having the desired particle size may be relatively small. The yield of the process can also be relatively low (considerable loss of product can be caused by its adherence to the walls of the apparatus used). Another disadvantage is that in the case of solvated products, the conditions used can cause loss of solvent, with a change in the crystalline structure and consequent formation of polymorphs. Another undesirable characteristic of micronised products is that the surface of the particles generated is often mainly amorphous, so that they tend with time to be converted into the more stable crystalline state, which may be different from the original state. The harder the conditions and the longer the micronization time, the greater the degree of amorphization. This drawback is particularly significant in the case of active ingredients which need to be resuspended in water. Materials which are even only partly amorphous are more liable than crystalline materials to moisture uptake (Hancock et al. J. Pharm. Sci. 1997, 86, 1-12), and this has adverse effects on active ingredients whose chemical stability is particularly sensitive to the humidity content.
Another drawback of micronization processes is that they require high energy and therefore require containment and other measures to avoid the risk of explosion.
Another problem which may affect micronised products, when formulated as suspensions, is an increment of the particle size over time as a result of total or partial recrystallisation of the small quantity of dissolved solute (Davis et al Int J Pharm 1, 303-314, 1978; Tiano et al Pharm Dev Tech 1, 261-268, 1996; Taylor et al Int J Pharm 153, 93-104, 1997). Such an increase can prejudice the efficacy of nebulisation and therapeutic efficacy because, as stated, particles with an MAD exceeding 5-6 μm are unable to reach the preferential site of action.
The phenomenon of ‘crystalline growth’ has been observed in particular for some steroids, such as BDP and flunisolide. When these active ingredients are formulated in suspension in inhaler propellants or aqueous vehicles, the crystals grow, leading to the formation of particles with a greater particle-size distribution than the original one. Another important requirement that must be met by pharmaceutical formulations designed for pulmonary delivery is sterility. This requirement is more and more recommended in various documents dealing with quality and safety of pharmaceutical products for a number of reasons, including the fact that the lungs are a particularly vulnerable organ of the human body, and many patients who use inhaled drugs have general health problems. The current trend is to produce inhalation formulations devoid of preservatives and bacteriostatics, as it has been reported in the literature that some of the substances commonly used for this purpose can give rise to allergic reactions or irritate the respiratory mucosae (Menendez R et al J Allergy Clin Immunol 84, 272-274, 1989; Afferty P et al Thorax 43, 446-450, 1988). Various processes can be used to manufacture sterile pharmaceutical formulations for inhalation. For example, the active ingredient can be pre-sterilised by dry heating or radiation, followed by preparation of the formulation under aseptic conditions as reported in WO 99/25359 and WO 00/25746, or the formulation can be pre-prepared and sterilised by treatment in an autoclave.
However, all the sterilisation methods reported for aqueous suspensions suffer from drawbacks or limitations. For example, pre-sterilisation methods require a subsequent stage of mixing of the active ingredient thus obtained with the other ingredients of the formulation, and preparation of the final formulation under aseptic conditions till the introduction into the final sterile container. Standard autoclaving treatments are unsuitable for aqueous suspensions of thermolabile corticosteroids (such as BDP), because they cause the chemical degradation of the active ingredient. These treatments can also give rise to agglomerates of particles of the active ingredient in the suspension which are difficult to redisperse, thus jeopardizing their therapeutic efficacy. Finally, in the case of suspensions, sterilizing filtration is not feasible because it requires the use of filters with a pore size less than or approximately equal to 0.2 micron, not compatible with the size of the disperded particles.
Various prior publications specifically refer to processes for obtaining active ingredients for pulmonary administration in a crystalline form by crystallisation from a solution in a suitable solvent upon addition of a proper anti-solvent.
GB 2107715, filed by Glaxo, describes the preparation of BDP monohydrate for use in the preparation of pharmaceutical compositions in dry powder form. The text states that BDP monohydrate can be prepared by crystallisation by slowly adding a solution of BDP in a water-miscible organic solvent, which may be ethanol, to water. After crystallization, the monohydrate may be isolated by, for example, filtration and washed and dried in conventional manner. The beclomethasone dipropionate monohydrate is then micronized to the desired particle size range by conventional techniques, for example using a ball mill or fluid energy mill or by ultrasonic means.
At least 90% in weight of the particles obtained are under 10 micron in size, and preferably 2-5 micron. The active ingredient is then formulated as a dry powder in a mixture with conventional solid diluents.
There is no teaching about how to make a sterile crystalline BDP monohydrate and/or pharmaceutical compositions in form of aqueous suspension for pulmonary delivery wherein the particle size distribution of the crystalline active ingredient does not change.
In the prior art, BDP monohydrate was only used to prepare suspensions in fluorinated propellants, to be delivered by metered dose inhalers, which do not need to be sterilised (patent applications WO 93/15741, WO 96 32345 and WO 99/53901 filed by Glaxo). Otherwise, BDP monohydrate has been used to prepare aqueous suspensions for nasal administration which are not sterile, and in order to be effective at the nasal mucosa level normally contain particles with a MAD greater than 10-20 micron, as proposed in the FDA guideline “Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action” issued in June 1999.
WO 90/03782, filed by the Upjohn Company, describes a process for the preparation of finely divided solids which involves dissolving the solid in a suitable solvent and adding the solution to an anti-solvent chosen from the group of supercritical fluids, compressed gases or condensed vapours. The preferred anti-solvent is carbon dioxide, while the solvent should be chosen according to the type of active ingredient.
U.S. Pat. No. 5,314,506, filed by Merck, claims a process for crystallisation of an organic pharmaceutical compound which comprises contacting one or more jet streams of a feed solution of the compound with one or more jet streams of an anti-solvent in conditions of high turbulence and with sufficient linear velocity to produce crystals with a diameter equal to or less than 25 micron. One of the jet streams optionally includes a surfactant, to prevent agglomeration of the particles.
WO 96/32095, filed by Astra, discloses a process for producing a pharmaceutical powder for inhalation with crystalline particles having a diameter of less than 10 micron which involves preparing a saturated or supersaturated solution of active ingredient and causing it to collide, in the form of a jet stream or droplets obtained through a nozzle or porous filter, with an anti-solvent under agitation. Methanol, isopropanol, dimethylsulphoxide, dimethylformamide and others can be used as organic solvents in the case of water-insoluble active ingredients. The text states that the process preferably takes place at a low temperature (below 25° C., and preferably between 0 and 5° C.). The examples refer to budesonide.
U.S. Pat. No. 5,314,506 and WO 96/32095 require isolation of the products before preparation of the final formulation, and are therefore incompatible with a continuous production process. The applicant has also demonstrated that due to the Venturi effect, the delivery of a solution as a spray through a nozzle leads to cooling of the organic solution, which in turn can cause crystallisation of the active ingredient and clogging of the nozzle under supersaturated conditions.
In WO 00/25746, filed by the applicant, aqueous suspensions for nebulisation based on a micronised steroid designed for inhalation, sterilised with gamma rays are described. The process basically involves a first stage of preparation in a turboemulsifier of an aqueous solution which constitutes the vehicle and contains suitable excipients, followed by the addition of the sterile micronised active ingredient and its dispersion at atmospheric pressure in the same turboemulsifier. The dispersion of the active ingredient in the aqueous phase may be subjected to an additional high-pressure homogenising treatment which further reduces the average size of the particles in suspension. The examples refer to BDP.
WO 01/49263, filed by Orion, relates to a process which involves: i) preparing a solution or suspension of active ingredient; ii) atomizing it to create droplets; iii) suspending said droplets in an inert gas which acts as carrier gas; iv) passing them through a heated tube flow reactor; v) collecting the particles with conventional techniques.
The invention is designed for active ingredients delivered by inhalation, with crystalline, spherical, rough, uncharged particles. This process is incompatible with a continuous production process. The passage through a tube flow reactor also involves a heating stage, which may not be compatible with thermolabile substances such as some steroids designed for inhalation.
WO 00/53282, filed by Smithkline Beecham, discloses a process for the continuous crystallisation of an organic compound which involves contacting a solution of active ingredient with an anti-solvent or colder solvent, or a suitable solution of an acid or base, and separating the crystals formed. The process preferably takes place in conditions of turbulence, and precipitation preferably takes place in less than 1 minute, and even more preferably in less than 5 seconds. The examples relate to eprosartan methanesulphate and nabumetone, two active ingredients unsuitable for administration by inhalation. For the former, the preferred solvent is acetic acid and the preferred anti-solvent is tert-butyl methyl ether or ethyl acetate. For the second active ingredient, the preferred solvent is 2-propanol, and the preferred anti-solvent is water.
WO 01/14036, filed by Aventis, claims a method for the preparation of drug particles which involves: i) dissolving the active ingredient in a solvent; ii) collision with an anti-solvent under conditions of turbulence followed by rapid precipitation of the active ingredient in the form of crystalline particles with a controlled diameter. This process is characterised in that the velocity of the opposing streams must exceed 50 m/sec, the ratio between anti-solvent volume and solvent volume must be >2:1 (preferably between 15:1 and 30:1), and the angle of collision between the two streams must preferably be less than 20 degrees. The invention is designed to produce drugs for inhalation with a final diameter of between 2 and 5 micron. Triamcinolone acetonide is indicated as the preferred active ingredient. There is no teaching relating to obtaining a sterile product, and in any event the process is incompatible with a continuous production process.
Various patent applications filed by Glaxo (WO 00/38811, WO 01/32125, WO 02/00198 and WO 02/00199) relate to processes for the preparation of crystalline particles of a substance which comprises the following stages: i) mixing a solution of active ingredient with an anti-solvent in a continuous-flow cell to generate a suspension; ii) filtering the suspension so as to isolate the particles with a diameter of between 1 and 10 micron, and preferably under 5 micron; iii) isolating and collecting the particles using techniques such as freeze-drying. In particular, the applications relate to conditions of isolation of the products (and consequently elimination of the solvents) which prevent crystalline growth of the particles during the isolation process.
The examples refer to fluticasone and salmeterol.
In WO 00/38811 and WO 02/00199 it is expressly stated that when the active ingredient is BDP, industrial methylated spirits (IMS) will preferably be used as organic solvent.
Here again, unlike the present invention, the processes always involve isolation of the products before preparation of the final formulation, and are therefore incompatible with a continuous production process.
In view of all these drawbacks, it would be a great advantage to provide a process which overcomes or at least mitigates the limitations of the technical solutions proposed in the prior publications.